A leading cause of death in the United States is heart disease. About one million persons in the United States die of heart disease each year. Heart disease is a combination of many diseases. The principal cause of heart disease is atherosclerosis which is a vascular disease that results in narrowing of the arteries that provide oxygen and nutrient-rich blood to the heart. When blood supply is diminished appreciably, the pain of angina pectoris may be felt. Such pain is frequently exacerbated when the heart requires an unusually large amount of blood such as during emotional stress or exercise. When the heart is thus deprived of its oxygen supply, heart muscle tissue dies. The narrowing of the blood vessels by atherosclerosis is anatomically caused by the accumulation of atherosclerotic plaques on the walls of the blood vessels. These plaques may rupture off of the lining of the blood vessel and occlude downstream blood vessels resulting in an acute adverse coronary event leading to sudden unpredicted fatalities associated with myocardial infarction and stroke. Accordingly, there exists a need in the art for a prognostic method to predict future risk of adverse coronary events.
Prognostic indicators of future adverse coronary events are known; however, each has its own inherent limitations. Two such indicators that are related to vascular inflammation are myeloperoxidase (MPO) and C-reactive protein (CRP). Plasma levels of MPO derived from circulating neutrophils have been found to correlate with cardiovascular disease and risk of major adverse coronary events. Neutrophils undergo degranulation within the coronary vasculature in acute coronary syndromes and MPO is a predominant protein in human neutrophils that is released during degranulation. Functional polymorphisms in the promoter region of MPO that result in decreased MPO expression have also been associated with decreased risk for cardiovascular disease. Blood and leukocyte levels of MPO serve as independent predictors of angiographically significant coronary artery disease. Recently, MPO has been shown to be a biomarker for risk of future cardiovascular events in patients with acute coronary syndromes. Since plasma MPO levels increase prior to elevations in plasma troponin T (TnT, a marker of myocardial cell death) levels, it has been suggested that MPO may be involved in the pathophysiological sequelae of acute coronary events. In fact, the identification of MPO in the shoulder region of atherosclerotic plaques has suggested MPO's role in plaque instability. Furthermore, oxidants produced by MPO have profound effects on the matrix metalloproteinases that functionally impact plaque stability. The prognostic value of MPO as an indicator of future coronary events and the biochemical mechanisms that MPO activity can have on plaque stability suggest that biomarkers indicative of MPO catalytic activity may improve the prediction of future coronary events. However, the use of MPO as a prognostic indicator is limited since the dynamic change in levels of MPO in the blood is only 1-2 fold and therefore does not allow for measurement of the catalytic or amplified response of MPO activity. Accordingly, there is a need in the art for a diagnostic method to predict future risk of adverse coronary events that is indicative of the catalytic or amplified response of MPO activity.
A second indicator of future adverse coronary events is C-reactive protein (CRP) which is an acute phase reactant and a sensitive, but non-specific marker, of inflammation that is enriched in atherosclerotic lesions. The use of CRP as a blood-borne marker that predicts CAD risk has become part of routine preventive risk assessment. However, a limitation of CRP as a blood-borne biomarker is the high incidence of false-positive results due to infections that are unrelated to cardiovascular disease. Accordingly, there is a need in the art for a specific biomarker of adverse coronary events that is not as easily influenced by other events such as infection that may falsely contribute to elevated levels of the indicator.